Semipermeable membranes play an important part in industrial processing technology and other commercial and consumer applications. Examples of their applications include, among others, biosensors, transport membranes, drug delivery systems, water purification systems, optical absorbers, and selective separation systems for aqueous and organic liquids carrying dissolved or suspended components.
Generally, semipermeable membranes operate in separation devices by allowing only certain components of a solution or dispersion to preferentially pass through the membrane. The fluid that is passed through the membrane is termed the permeate and comprises a solvent alone or in combination with one or more of the other agents in solution. The components that do not pass through the membrane are usually termed the retentate. The permeate and/or retentate may provide desired product.
Membranes are one of the most common and economically efficient methods to purify active pharmaceutical ingredients (API) in industry and provide a critical alternative to distillations, recrystallizations, and column chromatography (B. Schmidt, et al., Org. Process Res. Dev. 2004, 8, 998-1008; and S. Muller, et al., Eur. J. Org. Chem. 2005, 1082-1096). Distillations require that an API be stable to elevated temperatures and require significant amounts of energy to complete. Recrystallizations often result in APIs with high purities, but not every molecule can be recrystallized and the recyrstallization conditions are often difficult to optimize and scale up to an appropriate level. In addition, the formation of multiple crystalline isomorphs is poorly understood and results in APIs with different delivery characteristics in the body. Column chromatography is often used in the early discovery and development of APIs due to its simplicity and success, but it is not widely used for large scale production of APIs due in part to the large volumes of solvents that are used which necessitate further purification.
In contrast, the use of nanoporous membranes to purify APIs can be readily scaled up to purify large quantities of product, use little energy, and does not require large amounts of solvent (H. P. Dijkstra, et al., Acc. Chem. Res. 2002, 35, 798-810; M. F. J. Dijkstra, et al., J. Mem. Sci. 2006, 286, 60-68; J. Geens, et al., Sep. Sci. Technol. 2007, 42, 2435-2449; C. J. Pink, et al., Org. Proc. Res. Dev. 2008, 12, 589-595; and P. Silva, et al., Adv. Membr. Technol. Appl. 2008, 451-467). The use of nanoporous membranes in industry is common in aqueous separations or to purify gasses by pervaporation, but nanoporous membranes are used less commonly with organic solvents. A breakthrough was realized in 1990 when nanoporous membranes based on “organic solvent nanofiltration” (OSN) membranes were used in an ExxonMobil refinery to separate oil from dewaxing solvents (R. M. Gould, et al., Environ. Prog. 2001, 20, 12-16). The next generation of OSN membranes based on cross-linked polyaniline, polyimides, and other polymers and sold as StarMem™, Duramem™, and PuraMem™ have been developed that function in a wide range of organic solvents and separate organic molecules dissolved in organic solvents (D. A. Patterson, et al., Desalination 2008, 218, 248-256; Y. H. See-Toh, et al., J. Mem. Sci. 2008, 324, 220-232; Y. H. S. Toh, et al., J. Mem. Sci. 2007, 291, 120-125; and L. G. Peeva, et al., In Comprehensive membrane science and engineering; Drioli, E., Giorno, L., Eds.; Elsevier: Boston, 2010; Vol. 2, p 91-111).
All OSN membranes report values for the “molecular weight cutoff” (MWCO) that correspond to the molecular weight where molecules transition from having high to low values of permeation (Y. H. S. Toh, et al., J. Mem. Sci. 2007, 291, 120-125; and L. G. Peeva, et al., In Comprehensive membrane science and engineering; Drioli, E., Giorno, L., Eds.; Elsevier: Boston, 2010; Vol. 2, p 91-111). Simply, molecules below the MWCO permeate the membranes but molecules above the MWCO have significantly reduced permeation and are retained. The use of membranes that feature a MWCO has limitations for the separation of catalysts from APIs because the ligands on a catalyst often have molecular weights that are similar to that of the product. Thus, ligands such as PPh3 (MW: 262 g mol−1), PCy3 (MW: 280 g mol−1), and binol (MW: 286 g mol−1) can be very challenging to separate from APIs with similar molecular weights or impossible to separate if an API has a higher molecular weight.
The state-of-the-art membranes to separate catalysts from the products of reactions are based on highly cross-linked organic polymers that function in a range of organic solvents. For instance RuBINAP catalyst (molecular weight 795 g mol−1) was retained by OSN membranes at levels of approximately 98% for multiple cycles and was active for long periods of time (D. Nair, et al., Org. Proc. Res. Dev. 2009, 13, 863-869). The product was allowed to permeate the membranes and was isolated on the side of the membrane opposite of the catalyst. Part of the success of this project was the high molecular weight of the catalyst compared to the product (molecular weight 160 g mol−1) which allowed the catalyst to have a molecular weight significantly higher than the MWCO of the membrane (220 g mol−1).
In other work, the flux of trialkylamines (i.e. NR3 where R is methyl, ethyl, propyl, etc) through commercially available OSN membranes (StarMem™ membranes) were studied (D. A. Patterson, et al., Desalination 2008, 218, 248-256). This study described perplexing results because even though the molecular weight cutoff was 220 g mol−1, only 19% of tridodecylamine (molecular weight 522 g mol−1) was retained (81% permeated the membrane). Also, when the system was studied using cross-flow, the rejection rate for all of the trialkylamines was much poorer than expected. The authors concluded that the use of a molecular weight cutoff for trialkylamines and the StarMem membranes was not useful and gave misleading predictions.
OSN membranes have an important role in the chemical industry, but they have two limitations that hinder applications in many commercial syntheses of small molecules. First, to be effective there must be a large difference between the molecular weight of the catalyst and the organic product. The molecular weights of many common ligands range from a couple to several hundred grams per mole and would not provide enough difference in molecular weight to separate them from products with similar or higher molecular weights. Second, the MWCO of a membrane is defined as the molecular weight at which 90 to 98% of the solute is rejected; thus, significant amounts of a molecule may pass through these membranes even if the molecular weight is larger than the cutoff.
Other membranes composed of nanopores etched in polycarbonate, zeolites, and metal-organic frameworks have been fabricated by others that can separate organic molecules. Zeolites are well known for distinguishing molecules based on size, but they are not used as membranes for molecules with the dimensions described in this proposal. Nanopores etched in polycarbonates have found some success, but the molecular size cutoffs are typically not sharp and the membranes suffer from low flux, fouling, and degradation with time (A. Asatekin and K. K. Gleason Nano Lett. 2011, 11, 677-686; K. B. Jirage, et al., Science 1997, 278, 655-658; C. R. Martin, et al., J. Phys. Chem. B 2005, 105, 1925-1934; and M. Wirtz, et al., Chem. Rec. 2002, 2, 112-117). Metal-organic frameworks have been developed that use porphyrins to define pores, but all of these examples require either water as the solvent or only separate gasses (J. T. Hupp, et al., Langmuir 2006, 22, 1804-1809; R. Q. Snurr, et al., AIChE Journal 2004, 50, 1090-1095, B. Chen, et al., Acc. Chem. Res. 2010, 43, 1115-1124; D.-H. Liu and C.-L. Zhong J. Mater. Chem. 2010, 20, 10308-10318; U. Mueller, et al., J. Mater. Chem. 2006, 16, 626-636; K. M. Thomas Dalton Tran. 2009, 1487-1505; D. Zhao, et al., Acc. Chem. Res. 2011, 44, 123-133; and R. Zou, et al., CrystEngComm 2010, 12, 1337-1353).
PDCPD synthesized from the polymerization of commercially available dicyclopentadiene and the Grubbs catalyst is a relatively new material (M. Perring and N. B. Bowden Langmuir 2008, 24, 10480-10487; J. K. Lee, et al., J. Polym. Sci., Part B: Polym. Phys 2007, 45, 1771-1780; L. M. Bellan, et al., Macromol. Rap. Comm. 2006, 27, 511-515; A. D. Martina, et al., J. Appl. Polym. Sci. 2005, 96, 407-415; and J. D. Rule and J. S. Moore Macromolecules 2002, 35, 7878-7882). This polymer is cross-linked and forms a solid, hard material that, when synthesized by other catalysts, is used in the fabrication of the hoods of semitrucks and snowmobiles.